To safeguard the proteomic integrity, cells rely on the proteasome to degrade aberrant polypeptides and the lysosomes to degrade large insoluble protein aggregates. However, it is unclear how cells remove defective proteins that have escaped degradation owing to proteasome insufficiency or dysfunction in the lysosome. By study the function of USP19, an endoplamsic reticulum-associated deubiquitinase, we have uncovered a pathway termed misfolding-associated protein secretion. This process uses USP19 to preferentially export aberrant cytosolic proteins. Intriguingly, the catalytic domain of USP19 possesses an unprecedented chaperone activity, allowing recruitment of misfolded proteins to the ER surface for deubiquitylation. Deubiquitylated cargos are encapsulated into ER-associated late endosomes and secreted to the cell exterior. USP19-deficient cells cannot efficiently secrete unwanted proteins and grow more slowly than wild-type cells on exposure to a proteasome inhibitor. Together, our findings delineate a protein quality control (PQC) pathway, which, unlike degradation-based PQC mechanisms, promotes protein homeostasis by exporting misfolded proteins through an unconventional protein secretion process.